Abstract
Purpose :
The crystalline lens gradually becomes less elastic and opaque with age. These structural changes, primarily due to protein misfolding and aggregation, result clinically in presbyopia in the 40s and cataract in later life. This progressive loss of visual function is referred to as Dysfunctional Lens Syndrome (DLS). The crystallins (α, β and γ) are the most abundant lens proteins, however these proteins don’t regenerate and, must remain soluble throughout life. The α-crystallins act as chaperones for the β and γ-crystallins keeping them in their native soluble confirmation. As the lens ages, the α-crystallins break down from its natural soluble dimer confirmation into monomers and lose their chaperone activity. 25-Hydroxycholesterol (25-HC) is a small molecular chaperone that binds to α-crystallin and stabilizes its natural soluble dimer confirmation.
Methods :
Eight senior primates (median age 19 years) received a single 50-µL intravitreal injection of 3% 25-HC suspension through a 27-gauge needle in the study eye (SE). The uninjected, non-study eye (NSE) served as a control. The Lens Opacities Classification System (LOCS III) nuclear opalescence scores were graded by a masked observer at the slit lamp beginning 2 months before IVT and 8 weeks after. Scores were independently verified by an independent grader from lens photographs. Paired Student’s ‘T’ tests comparing follow-up scores to baseline (Day 1) were performed.
Results :
There was a statistically significant change from baseline in lens opacity in the SE beginning at day 8 and lasting to day 57. There were no significant changes in the NSE. At baseline, the average LOCS III score was 2.7 ± 0.2 and decreased maximally to 1.4 ± 0.3 by day 43. Anterior chamber inflammation was observed clinically in some eyes.
Conclusions :
This study demonstrates that the small molecule α-crystallin chaperone, 25-HC, can reverse spontaneous nuclear cataract in primates, a relevant model for human cataract, and provides proof-of-concept for this lens modulation approach. However, sterols are highly insoluble, penetrate the lens poorly and cause ocular toxicity. Visus is developing non-sterol α-crystallin chaperones with more favorable pharmaceutical properties.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.